Lycium barbarum, also known pharmaceutically as Fructus lycii and commonly known as Chinese wolfberry fruit or lycium fruit, is native to Asia (Ninxia, Gansu, Qinghai, Tibet, Inner Mongolia, and Hebei), but widely cultivated in much of the United States. For thousands of years, people in Asia have used lycium fruits and licorice to help maintain good health. Lycium is a Chinese herb that helps improve vision and prevent headaches and dizziness caused by liver and kidney deficiencies. Also lycium has been shown effective in treating mild diabetes. It is believed that Lycium barbarum can improve and regulate the immune system; contain anti-aging and anti-cancer properties; lower blood lipid levels; protect liver function; improve white blood cell counts during chemotherapy; lower blood sugar; and lower blood pressure.
Angiogenesis is a process through which new blood vessels arise by outgrowth from pre-existing blood vessels. In this process, endothelial cells become detached from the basement membrane as proteolytic enzymes degrade this support. These endothelial cells then migrate out from the parent vessel, divide, and form a newly differentiated vascular structure (Risau, (1997) Nature 386:671-674; Wilting et al., (1995) Cell. Mol. Biol. Res. 41(4): 219-232). A variety of different biological factors have been found to function in controlling blood vessel formation (Bussolino et al., (1997) Trends in Biochem Sci 22(7): 251-256; Folkman and D'Amore, (1996) Cell 87:1153-1155). These include proteins with diverse functions such as growth factors, cell surface receptors, proteases, protease inhibitors, and extracellular matrix proteins (Achen and Stacker, (1998) Int. J. Exp. Pathol. 79:255-265; Devalaraja and Richmond, (1999) Trends in Pharmacol. Sci. 20(4): 151-156; Hanahan, (1997) Science 277:48-50; Maisonpierre et al, (1997) Science 277:55-60; Suri et al, (1996) Cell 87:1171-1180; Sato et al, (1995) Nature 376:70-74; Mignatti and Rifkin, (1996) Enzyme Protein 49:117-137; Pintucci et al., (1996) Semin Thromb Hemost 22(6) 517-524; Vernon and Sage, (1995) Am. J. Pathol. 147(4): 873-883; Brooks et al., (1994) Science 264:569-571; Koch et al., (1995) Nature 376:517-519).
Angiogenesis participates in essential physiological events, such as development, reproduction and wound healing. Under normal conditions, angiogenesis occurs in a carefully controlled or highly regulated manner during embryonic development, during growth, and in special cases such as wound healing and the female reproductive cycle (Wilting and Christ, (1996) Naturwissenschaften 83:153-164; Goodger and Rogers, (1995) Microcirculation 2:329-343; Augustin et al., (1995) Am. J. Pathol. 147(2): 339-351).
However, many diseases or health disorders, e.g. cancer metastasis, diabetic retinopathy, rheumatoid arthritis and other inflammatory diseases such as psoriasis, are driven by persistent unregulated angiogenesis (Folkman, (1995) Nature Med. 1(1): 27-31; Polverini, (1995) Rheumatology 38(2): 103-112; Healy et al., (1998) Hum. Reprod. Update 4(5): 736-396). For instance, in rheumatoid arthritis, new capillary blood vessels invade the joints and destroy the cartilage. In diabetic retinopathy, new capillaries in the retina invade the vitreous, bleed, and cause blindness. Therefore, effective therapeutic intervention, control and/or inhibition of pathological angiogenesis can alleviate a significant number of diseases.
The angiogenic process provides points for therapeutic intervention to control vascular formation in vivo. Protein inhibitors of angiogenesis such as angiostatin (O'Reilly et al., (1994) Cell 79(2): 315-328) and endostatin (O'Reilly et al., (1997) Cell 88(2): 277-285), that control vascular formation in experimental models, have been discovered. Nevertheless, such protein therapeutics are expensive to produce and have been found to be difficult to formulate and deliver in subjects. At present, protein angiogenesis inhibitors have yet to be developed into pharmaceuticals for patient therapy. Thus, there exists a need for therapeutic substances that can be safely administered to a patient and be effective at inhibiting, interfering, modifying and/or controlling the pathological growth of vascular endothelial cells. The present invention provides compositions and methods that are useful for this purpose.